The cardiac glycosides and the sympathomimetic amines are the principal inotropic agents used in the management of congestive heart failure. Although the cardiac glycosides, especially digitalis, are among the most frequently prescribed drugs, they have numerous liabilities such as a low therapeutic index and erratic absorption, and are associated with life-threatening arrhythmias and deleterious drug-drug interactions. In addition, many patients either do not respond, or become refractory to these agents. The sympathomimetic amines, such as dopamine and epinephrine, have limited utility due to positive chronotropic effects, arrhythmogenic properties, and oral ineffectiveness.
More recently, new classes of inotropic agents have been found. Among these, certain 2-phenylimidazo[4,5-b]pyridines (U.S. Pat. Nos. 3,985,891 and 4,327,100) have been shown to possess inotropic and anticoagulant activity. U.S. Pat. Nos. 4,299,834 and 4,353,909 describe similarly substituted purine and 6-hydroxy-imidazo[4,5-b]pyridine derivatives.
Weidenhagen and Weeden (Ber., 71B, 2347 (1938); CA 33:984(6)) describe the preparation of 2-phenylimidazo[4,5-c]pyridine and the p-methoxyphenyl and p-aminophenyl analogs.
Middleton and Wibberly (J. Het. Chem., 17, 1757 (1980)) describe the preparation of a variety of substituted imidazopyridines including o-hydroxy-, o-nitro-, m-chloro-, p-chloro-, p-nitro-, and p-amino-substituted 2-phenylimidazo[4,5-c]pyridines, and o-methyl-, o-chloro-, m-chloro-, m-nitro-, p-methyl-, p-bromo-, p-chloro-, p-nitro-, and m,m-dinitro-substituted 2-phenyl-4-chloroimidazo[4,5-c]pyridines. Some of these compounds were found to be active mutagens in the Ames test (Middleton, et al., Mutation Research, 78, 323 (1980)).
Both Lee, et al., Org. Prep. Proced. Int., 12 (3-4), 234 (1980) and Haskell, et al., J. Med. Chem., 13(4), 697 (1970) describe the preparation of 2-(2-aminophenyl)imidazo[4,5-c]pyridine.
Yutilov and Shcherbina, Deposited Doc., 1980, VINITI 5441-80, reported in CA 96:68900f, have prepared 2-phenylimidazo[4,5-c]pyridines substituted in the phenyl ring with hydrogen, 4-methoxy, 4-dimethylamino, 4,3- and 2,3-hydroxy-methoxy, and 3,4- and 2,5-dimethoxy.
The preparation of 2-(2-hydroxyphenyl)imidazo[4,5-c]pyridine was reported by Spector and Joullie' in J. Het. Chem., 6(5), 605 (1966).
The present invention provides for a series of 2-phenylimidazo[4,5-c]pyridines, their formulations, and their use as orally effective positive inotropic agents which have minimal effects on blood pressure and heart rate. The compounds also possess vasodilitation, bronchodilation, and anticoagulant activities.